Mathematical modeling combined with experiment has led to increased understanding of the processes that underlie HIV-1 infection and the development of improved therapies. Nevertheless HIV has not been eradicated from infected individuals. Here we propose to develop new models of HIV infection that will help inform vaccine and microbicide development. The models will incorporate both cell-mediated and humoral immune responses to infection, and aim toward understanding the roles that CD8 T cells and antibodies play in the natural defense against HIV. We will also develop stochastic models of the first events in infection in order to gain insight into the earliest processes that occur when virus first enters a person. Some of the early events in infection involve depletion of CD4+ T cells in the gut. These events will be modeled as well as the dynamics of reconstitution of CD4 T cells in the gut due to the effects of antiretroviral therapy. Lastly, models with multiple organs, such as gut, liver, lymph nodes, etc. will be used to understand how HIV distributes throughout the body and how it is cleared at different sites in the body. Infection by hepatitis C virus (HCV) and hepatitis B virus (HBV) continue to cause liver failure and hepatocellular carcinoma in infected individuals. Understanding the basis of pathogenesis and the development of potent antiviral therapies for these viruses lag behind our advances in HIV. We propose to expand our efforts in modeling HCV and HBV in vivo kinetics and the effects of antiviral therapy. In the case of HCV we propose to focus on modeling new treatments with specifically targeted anti-HCV agents, such as HCV polymerase and protease inhibitors. With these new agents the development of resistance is a great concern and we will expand models of viral kinetics and treatment that we have previously developed and validated so as to incorporate viral mutation and the development of drug resistance. We will also perform calculations aimed at understanding how prevalent pre-existing drug resistance mutations should be as well as use modeling to develop better treatment strategies, Lastly, for the case of HBV, we aim to understand why HBV infection can be cleared during primary infection in adults. We will develop models of primary HBV infection that include both non-cytolytic responses and antibody responses. We also plan to develop a new generation of on treatment models that follow not only the dynamics of HBV DNA but also HBe antigen and Hbs antigen, molecules that are used in clinical practice to access response to therapy but whose dynamics have been well studied. PUBLIC HEALTH RELEVANCE: The goals of this project are to expand our understanding of viral and lymphocyte dynamics as they pertain to HIV/AIDS as well as to hepatitis B and hepatitis C virus infections. These three viruses are major public heath threats with HIV currently infecting about 33 million people world- wide, while hepatitis B and C currently infect about 300 million and 170 million people, respectively. By developing mathematical models of these infections and their treatment we aim to improve our basic understanding of disease pathogenesis and improve protocols for antiviral therapy.